Pancreatic beta cells secrete insulin in an oscillatory pattern that is disrupted during the progression from glucose intolerance to Type 2 diabetes (T2D) in humans. Disrupted insulin pulsatility in turn contributes to the etiology of the disease. However, the mechanisms underlying the beta cell oscillations that mediate pulsatile secretion remain undetermined. Our functional studies of islet oscillations have resulted in increasingly powerful mathematical models that predict experimentally determined islet behaviors. This iterative approach has led to the Integrated Oscillator Model (IOM), which incorporates more complex interactions between autonomous glycolytic oscillations (AGO), driven by phosphofructokinase (PFK), and passive glycolytic oscillations (PGO), driven by calcium feedback onto glycolysis, and how both interact with ion channels. AGOs are hypothesized to mediate oscillations in basal secretion and also mixed fast/slow (compound) oscillations (CO), which are common but have defied explanation by any other models and may have particular advantages for beta cell glucose sensing. We will determine how these different modes combine to optimize beta cell responses to glucose over a range of metabolic conditions. Additionally, our newest data suggest AGOs may be mediated by phosphofructokinase P (PFK-P; platelet type) rather than PFK-M (muscle type). Building on this substantial progress, we will test our central hypothesis that islet oscillations are produced by coupled metabolic and electrical actions linked by intracellular Ca2+ and ATP and test whether GOs are autonomous or passive, and under what conditions, using the IOM to guide us. We will determine how mouse islet mechanisms pertain to human, and whether T2D islets have altered mechanisms. We will determine how ATP-sensitive K channel (K(ATP) channel) trafficking contributes to glucose?s action on beta cells. Electrophysiology, [Ca2+] imaging, modeling, and novel optical probes will be used to systematically study islets from wild type mice, mice lacking K(ATP) channels (SUR1-/-), other mouse models and islets from normal and T2D humans